tbuckley/cabot-search huggingface dataset:
Radical radiotherapy for muscle-invasive bladder cancer: A single centre experience.
Authors: Mayumi Forster, Ami Mehta, Amy Clifford, Sarah Needleman, Sonia Mansukhani, Mark Prentice
Journal: Journal of Clinical Oncology (2023)

519 Background: Muscle-invasive bladder cancer (MIBC) is managed with radical cystectomy or (chemo)radiotherapy ((C)RT), CRT offers the chance of cure alongside organ preservation. Patients presenting with MIBC are often elderly and frail, with comorbidities precluding cystectomy and systemic treatment. We report outcome data for our institution of patients treated with radical (C)RT. Methods: Patients with T2-4N0 MIBC diagnosed between December 2014 and December 2021 were retrospectively identified from the radiotherapy planning system. Baseline demographic, clinical and follow up data were collated from electronic patient records. Results: 54 patients were identified. Mean patient age was 78.5 (range 47 – 94); 51 patients had urothelial cancer and 3 squamous cell carcinoma. 20 patients had evidence of carcinoma in situ (CIS) at diagnosis. 19 patients had neoadjuvant chemotherapy (NACT) (13 patients had cisplatin-gemcitabine, 6 patients had carboplatin-gemcitabine). 12/19 patients completed 3 cycles of NACT, 7 patients received 1-2 cycles. 24/54 patients had concurrent chemotherapy (6 patients receiving mitomycin-5-FU, 17 weekly gemcitabine and 1 weekly cisplatin). 14/24 patients completed concurrent chemotherapy as planned. Of the 24 patients treated with CRT, 18 had NACT. 12 patients received 64 Gy 32 fractions, 2 received 60 Gy 30 fractions, and 40 received 55 Gy 20 fractions. All except 1 patient completed the prescribed course. With a median follow up of 9.4 months (range 0.7-79 months), 3-year overall survival was 43% for all patients; 63% with CRT and 21% with RT alone (log-rank test p=0.0052 HR 3.15 (95% CI 1.48-6.7)). At 3 years 49% were free of recurrence (distant or local); 72% with CRT and 25% with RT alone (log-rank test 0.0079 HR 3.12 (95% CI 1.38-7.01)). 3yr OS and % free of recurrence were not impacted by the presence of CIS. OS was 46% with CIS and 41% without (log-rank test p=0.6649); 3yr % free of recurrence was 43% with CIS and 49% without (log-rank test p=0.4055). Median time to recurrence with CIS was shorter at 13.3 months vs 26.1 months. Conclusions: Radical radiotherapy to the bladder is an effective option for the treatment of MIBC and should be routinely discussed with patients. Patients should be treated with CRT as opposed to RT alone as both OS and RFS are significantly improved. Ensuring patients are fit to receive systemic treatment alongside RT may require prehabilitation in this elderly and more co-morbid group.
Rucaparib for metastatic castration-resistant prostate cancer (mCRPC): TRITON3 interim overall survival and efficacy of rucaparib vs docetaxel or second-generation androgen pathway inhibitor therapy.
Authors: Alan Haruo Bryce, Josep M. Piulats, M. Neil Reaume, Peter James Ostler, Raymond S. McDermott, Joel Roger Gingerich, Elias Pintus, Srikala S. Sridhar, Wassim Abida, Gedske Daugaard, Axel Heidenreich, Laurence E. M. Krieger, Brieuc Sautois, Andrea Loehr, Darrin Despain, Jowell Go, Simon Paul Watkins, Simon Chowdhury, Charles J. Ryan, Karim Fizazi
Journal: Journal of Clinical Oncology (2023)

18 Background: TRITON3 (NCT02975934) is a randomized, multicenter, open-label, phase 3 study of rucaparib vs physician’s choice (docetaxel [DTX], abiraterone [ABI] or enzalutamide [ENZ]) in patients (pts) with chemotherapy-naïve mCRPC with BRCA1/2 (BRCA) or ATM alterations. It was previously reported that rucaparib significantly improved the primary endpoint of radiographic progression-free survival (rPFS) vs physician’s choice in pts with BRCA or ATM alterations. We report here the interim overall survival (OS) and also report on efficacy of rucaparib compared individually with either DTX or ABI/ENZ. Methods: Pts had disease progression after 1 prior second-generation androgen pathway inhibitor therapy in any setting and were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX, ABI or ENZ. An ordered step-down multiple comparisons procedure was used to control the overall error rate. OS was a key secondary endpoint with rPFS as the primary endpoint tested first in the BRCA subgroup, then the intent-to-treat (ITT) population. Subgroup analyses based on physician’s choice were exploratory. Results: As of August 25, 2022, 302 pts with BRCA and 103 pts with ATM alterations were randomized. OS maturity was 54% in the BRCA subgroup and 59% in the ITT population. rPFS and OS are shown. The most frequent treatment-emergent adverse event (TEAE) in the rucaparib, DTX and ABI/ENZ groups was asthenia/fatigue (61.1%, 67.6% and 57.6%, respectively). The most frequent grade ≥3 TEAE in the rucaparib, DTX and ABI/ENZ groups was anemia (23.7%), neutropenia (14.1%), and hypertension (10.2%), respectively. Conclusions: Rucaparib significantly improved rPFS vs either DTX or ABI/ENZ; safety was consistent with prior reports. Interim OS results suggest a trend towards improvement for rucaparib vs DTX or ABI/ENZ in pts with mCRPC and BRCA alterations. Clinical trial information: NCT02975934 . [Table: see text]
Genomic determinants of patterns of failure in metachronous oligometastatic castration-sensitive prostate cancer.
Authors: Philip Sutera, Kim Van der Eecken, Amol Shetty, Yang Song, Theresa Hodges, Sofie Verbeke, Jo Van Dorpe, Valerie Fonteyne, Bram De Laere, Mark V. Mishra, Zaker Hamid Rana, Jason K. Molitoris, Matthew J. Ferris, Nicholas J Roberts, Daniel Y. Song, Theodore L. DeWeese, Kenneth J. Pienta, Matthew Deek, Piet Ost, Phuoc T. Tran
Journal: Journal of Clinical Oncology (2023)

238 Background: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state along the progression of metastatic disease in which patients experience improved outcomes compared to those with higher disease burden. Despite the generally more indolent nature, much heterogeneity still exists with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Here we correlate tumor genomics with modes of progression (MOP) and patterns of failure (POF) following treatment for omCSPC. Methods: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC, who underwent tumor next generation sequencing (NGS) with at least 1 year of follow-up. Descriptive POF and MOP were reported with respect to presence of genomic alterations in pathways of interest. Genomic pathways of interest included TP53, SPOP, WNT ( APC, CTNNB1, RNF43), DNA double strand break repair, cell cycle genes ( Rb1, CCND1–3, CDKN1B, and CDKN2A), and PI3K/AKT/mTOR. MOP were defined as oligoprogression (1-3 lesions), polyprogression (≥4 lesions), or long-term control (LTC, no radiographic progression at last follow-up). POF included location of lesions at first failure. Overall survival (OS) was calculated by the Kaplan-Meier method. Genomic associations with patterns/modes of failure were compared with chi-square test. Results: 221 patients were included for analysis with the majority having either 1 (47.5%) or 2 (27.3%) metastatic lesions at oligometastasis. 5-yr OS was associated with MOP 92% vs 89% vs 69% (p&lt;0.01) for LTC, oligo- and polyprogression respectively. TP53 mutations were associated with significantly lower rates of LTC (24.4% vs 46%, p&lt;0.01) and cell cycle mutations associated with high rates of polyprogression (36.7% vs 15.7%, p&lt;0.01). With respect to POF, bone failure was significantly more common within tumors harboring mutations in TP53 (41.2% vs 23.1%, p=0.01) and less common with SPOP mutations (4.2% vs 27.8%, p=0.02). Finally, visceral failures were more common in tumors harboring either WNT pathway (20% vs 5.1%, p&lt;0.01) or SPOP (17.4% vs 5.2%, p=0.04) mutations. Notably, SPOP and WNT pathway mutations cluster together (p&lt;0.01). Conclusions: Tumor genomics provides novel insight into patterns of failure and modes of progression following treatment for metachronous omCSPC. Patients with TP53 and cell cycle mutations have a higher likelihood of progression and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism.
Natural killer cell activity in patients with metastatic castration-resistant prostate cancer treated with enzalutamide.
Authors: Ahmed Zedan, Line Nederby, Lone Volmer, Christine Vestergaard Madsen, Bente E. Sørensen, Torben Hansen
Journal: Journal of Clinical Oncology (2023)

255 Background: Metastatic castration resistant prostate cancer (mCRPC) is the lethal stage for most patients with prostate cancer (PCa). The need for more reliable prognostic and predictive markers for the management of mCRPC is still unmet. The aim of this study was to elucidate the correlation between Natural Killer cell activity (NKA) and treatment outcome in mCRPC patients. Methods: Blood samples were collected prospectively from 87 patients with mCRPC who were treated by enzalutamide as first line treatment. Samples were collected, in NK Vue tubes, at baseline, and prior to each treatment cycle until treatment change. Tubes were placed in an incubator at 37°C within 15 minutes of sampling. Following 20-24 hours of stimulation the level of interferon-gamma (IFNγ) in the plasma was measured, by ELISA (NK Vue) as a surrogate for NKA. Outcomes data were included as endpoints. Results: At the time of biochemical response, plasma IFNγ decreased significantly compared to levels detected at baseline (z-score= 2.334, p=0.019). Additionally, the level of IFNγ was significantly lower at radiological response compared to values at biochemical progression (z-score=2.168, p=0.030). Regarding outcome data, the whole cohort was divided into four groups. In group 1 (n=41) the IFNγ level remained within a normal range (&gt;250 pg/mL), while in group 2 (n=8) it increased from an abnormal (&lt;250 pg/mL) to a normal level. In group 3 (n=13) it dropped to an abnormal level, and it remained at an abnormal level during treatment in group 4 (n=17). There was a significant difference between patients in group 2 and patients in the other three groups regarding both overall survival, radiological free survival and time to next treatment (HR= 3.98, p= 0.012, HR= 6.10, p=&lt; 0.001 and HR= 6.521, p= &lt; 0.001, compared to group 1 respectively). Conclusions: An inverse correlation between NKA and both treatment response and outcome was observed, suggesting a unique role of NK cells in late stage PCa treated with enzalutamide.
Financial toxicity and coping mechanisms in patients with metastatic prostate cancer: A pilot study.
Authors: Daniel D Joyce, Phillip J. Schulte, Eugene D. Kwon, Stacie B Dusetzina, David F. Penson, Jon Charles Tilburt, Stephen A. Boorjian
Journal: Journal of Clinical Oncology (2023)

125 Background: Assessments of financial toxicity among patients with metastatic prostate cancer are lacking. We sought to describe the prevalence and severity of financial toxicity, identify coping mechanisms, and assess characteristics that may be protective of financial toxicity among such patients at our institution. Methods: All patients evaluated in the advanced prostate cancer clinic at Mayo Clinic, Rochester, MN, were approached to complete a survey between February and May 2022. The survey consisted of three parts: 1) demographic, cancer, and treatment characteristics; 2) a coping mechanism questionnaire; and 3) The Comprehensive Score for Financial Toxicity (COST-FACIT) questionnaire. COST-FACIT scores range from 0-44, with lower scores signifying higher financial toxicity. Patients were defined as having either high (COST-FACIT score &gt;24) or low (COST-FACIT score ≤24) financial toxicity. Coping mechanisms were compared between patients with low and high financial toxicity using Fisher’s exact test. Multivariable linear regression was used to evaluate patient characteristics associated with high COST-FACIT scores. Results: Of the 786 patients approached, 417 (53.1%) completed the survey and 281 met inclusion criteria. The median COST-FACIT score was 30 (IQR 24-36). On multivariable analysis, characteristics associated with lower financial toxicity included older age, (estimate:0.36, 95%CI 0.21-0.52), applying for patient assistance programs (estimate:4.42, 95%CI 1.72-7.11), and an annual income of at least $100,000 (estimate:7.81, 95%CI 0.97,14.66). Patients with high financial toxicity were more likely to decrease spending on basic goods (34.6% vs. 2.5%, p&lt;0.001) and leisure activities (61.5% vs. 16.9%, p&gt;0.001), as well as use savings (61.5% vs. 16.9%, p&lt;0.001) to pay for their treatment. However, few patients stopped or partially filled their prostate cancer treatments due to cost. Conclusions: In this cross-sectional study of patients with metastatic prostate cancer, older age, higher income, and applying for patient assistance programs were associated with lower financial toxicity. Greater self-reported financial toxicity was associated with decreased spending on basic goods, leisure activities, and tapping into savings. On rare occasion they delayed or skipped treatment. These findings are important to inform treatment shared decision-making and supportive interventions to mitigate financial toxicity in metastatic prostate cancer.
Landscape of genomic alterations (GA) in urothelial bladder carcinoma (UBC) in patients of East Asian and South Asian ancestry.
Authors: Taylor Peak, Philippe E. Spiess, Roger Li, Petros Grivas, Andrea Necchi, Dean C. Pavlick, Richard S.P. Huang, Douglas I. Lin, Natalie Danziger, Joseph M Jacob, Gennady Bratslavsky, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2023)

567 Background: UBC is the 10 th most common cancer worldwide, with more than 550,00 new cases annually (WHO, International Agency for Research on Cancer, 2020). Rates vary by regions of the world, explained in part by the fact that different genetic ancestries demonstrate varying germline genetics, environmental exposures, and social risk factors. Methods: 8,728 UBC samples underwent hybrid capture-based comprehensive genomic profiling (CGP) to determine all classes of genomic alterations (GA), microsatellite instability (MSI) status, tumor mutational burden (TMB), and genomic trinucleotide signature. Predominant genetic ancestry was determined using a SNP-based approach using an algorithm trained on the 1000 Genomes data (Connelly et al. AACR 2018). Ancestry was classified as one of the five following categories: African (AFR), European (EUR), Central and South American (AMR), South Asian (SAS), or East Asian (EAS). Results: Of the cohort, 7,447 (85.3%) were EUR, 541 (6.2%) were AFR, 461 (5.3%) were of AMR, 74 (0.85%) were SAS, and 205 (2.3%) were EAS. Age, gender, genomic signature distributions, and MSI status (range 0.9%-1.5%) were similar in all cohorts. The frequency of TMB &gt;10 mutations/Megabase was similar in all cohorts (range 30.7%-39.1%) as was the median TMB (6.3 mutations/Megabase for all). At 67.6%, TP53 was the most frequent GA in SAS cohort. When compared with the non-SAS cohort, TERT GA were lower in the SAS cohort (58.1% vs 72.6%; p=0.06) as were GA in FGFR3 (9.5% vs 18.5%, p=0.25). In the EAS cohort, at 59.0%, GA in TP53 were the most common. TERT mutations were significantly lower in EAS compared to the non-EAS cohort (54.1% vs 72.9%; p &lt;0.001). When compared with the non-EAS cohort, PIK3CA alterations were significantly less common in the EAS cohort (12.7% vs 22.1%, p =0.005). GA in FGFR3 were similar in the EAS and non-EAS cohorts (16.6% vs 18.4%). There were no significant differences in genomic landscapes identified between the EAS and SAS cohorts when directly compared to one another. Conclusions: The results from this comprehensive genomic analysis of UBC in East Asian and South Asian patients provides important insight into the unique differences in the genomic landscapes that exist on a population level. These findings should motivate future investigators to include more diverse patient populations in clinical trials of targeted agents and immunotherapy strategies.
Drug-drug interactions (DDIs) in elderly patients with metastatic renal cell carcinoma (mRCC) treated with cabozantinib within the multicenter prospective trial ZEBRA/Meet-URO 9.
Authors: Alvise Mattana, Marzia Del Re, Davide Bimbatti, Sebastiano Buti, Melanie Claps, Marilena Di Napoli, Lucia Fratino, Daniele Santini, Mariella Sorarù, Francesco Grillone, Giulia Mazzaschi, Marco Maruzzo, Francesco Pierantoni, Melissa Ballestrin, Chiara De Toni, Eleonora Lai, Michele Dionese, Vittorina Zagonel, Umberto Basso
Journal: Journal of Clinical Oncology (2023)

648 Background: The oral tyrosine kinase inhibitor Cabozantinib (CABO) is frequently used to treat patients with metastatic RCC. Polypharmacy is common in elderly pts, thus several drug-drug interactions (DDIs) with cabozantinib may ensue. Methods: ZEBRA /MEET-URO 9 was a prospective, real world trial enrolling pts ≥ 70 years with mRRC treated with CABO at 13 Italian Oncology Centers. All concomitants drugs administered to pts were collected and categorized according to active principles and indication. DDIs were identified through a dedicated software (Lexicomp), scientific databases (Sider4.1) and published articles. Results: we enrolled 104 pts, median age 75.8 years (range 70.2-87.4 yrs). Overall, 91.4% of the cohort was treated at a reduced dose either upfront or due to side effects. Pts took a median of 6 concomitant drugs (IQR: 4-9), for a total of 131 active principles. Software analysis identified 4 DDIs (warfarin, apixaban, diltiazem and furosemide); whereas scientific reports allowed us to identify 15 additional DDIs involving metoprolol, nebivolol, olmesartan, amiloride, simvastatin, rosuvastatin, polyenoic omega-3 fatty acids, loperamide, metoclopramide, metformin, dutasteride, dexamethasone, prednisone, cetirizine and doxazosin. Seventy pts with potential DDIs experienced a trend for higher rate of grade 3-4 adverse events compared to other pts, although difference was not statistically significant (48.7% v 23.5 %, p=0.485). The table summarizes the main DDIs and suggestions to avoid or mitigate their effects Conclusions: the risk of DDIs was not negligible in our cohort of elderly mRCC pts treated with CABO, although the frequent dose reductions of CABO probably confounded their impact on toxicities. Unremitting attention to concomitant medications in the elderly is thus warranted. [Table: see text]
Effect of cerebral dopamine metabolism genetic polymorphism on patient-reported quality-of-life (QOL): An analysis of the E3805 CHAARTED trial.
Authors: Arjun Gupta, Yu-Hui Chen, Christopher Sweeney, David Frazier Jarrard, Elizabeth R. Plimack, Benjamin Adam Gartrell, Michael Anthony Carducci, Maha H. A. Hussain, Jorge A. Garcia, David Cella, Robert S. DiPaola, Alicia K. Morgans
Journal: Journal of Clinical Oncology (2023)

123 Background: QOL outcomes have been associated with specific genetic variants in neurotransmitter metabolism. One such variant associated with reduced symptoms in placebo studies is in the rs4680 SNP of Carboxy-O-Methyltransferase (COMT). This variant is associated with reduced COMT enzymatic activity, higher cerebral dopamine levels, and improved mood. The interaction between this germline variant and cancer-directed treatment on QOL is undefined. A priori, we hypothesized that the COMT rs4680 SNP would be associated with better pain and QOL patient reported outcomes (PROs), than wildtype (WT) COMT within the E3805 CHAARTED Trial. Methods: E3805 compared docetaxel + androgen deprivation therapy (ADT+D) vs ADT in patients with metastatic hormone sensitive prostate cancer (mHSPC). PROs were collected at baseline, 3, 6, 9, and 12 months. Blood samples were genotyped prior to treatment. We compared PROs between patients with COMT WT vs rs4680 SNP within treatment arms longitudinally. PROs include Brief Pain Inventory (BPI) classified as: no (0), minimal (1), or more (≥2) pain, and BPI interference (range 0-10, 0= no pain or interference), and the Functional Assessment of Cancer Therapy-Prostate (FACT-P, higher score= better QOL, clinically important difference (CID)= 6). Descriptive statistics were used to characterize QOL over time. Fisher’s exact test, Wilcoxon rank sum test and mixed effects models were used to evaluate the associations between SNP and QOL in each arm. Results: Of 790 participants, 550 with SNP data were included. In the ADT+D arm, SNPs were not associated with PROs at any time point. In contrast, in the ADT alone arm, when compared to WT, rs4680 was associated with less pain at 3 months, less interference at 3, 6 and 9 months, and better QOL at 6 months (met criteria for CID). Conclusions: The rs4680 SNP, often associated with higher cerebral dopamine levels and improved QOL, was associated with less pain and superior QOL among patients with mHSPC treated with ADT, but not chemohormonal therapy. This is the first hypothesis driven genotyping study to demonstrate that genetics are associated with QOL in patients with cancer, especially when treatment does not cause profound symptoms. Clinical trial information: NCT00309985 . [Table: see text]